We have extended this project now to include: Phosphatase and kinase inhibitors as well as immunomodulators. Based on our recent discovery of the driver of 92% of the death from ER(-) breast cancer, we have begun to test these in different models as well as develop new biomarkers. The three pronged approach: 1) Redox modulators in Inflammation 2) Phosphatase agonist and kinase inhibitors 3) Immune modulators with Radio- and Chemotherapy 1) Redox Inflammatory modulators: Non steroidal anti inflammatory drugs (NSAIDs) have been used in a wide range of treatments including cancer. Studies have shown that some types of cancer, like breast lung, prostate and colon cancer respond to NSAIDs. Given in conjunction with radiation and chemotherapy improve patient outcome. In cancer prevention studies NSAIDs and other cyclo-oxygenase inhibitors (COX-2) have shown 30-50% efficacy in preventing a variety of cancer. Despite these positive effects, it has been shown that NSAIDs can cause gut ulceration as well as increased risk of heart attacks and strokes. Despite the promise of COX- specific inhibitors the risk of thrombosis remained. More recently, a new class of NSAIDs have emerged which can release nitric oxide and other small redox active molecules (hydrogen sulfide) which overcome both these side effects. In conjunction with CCR PIs and chemist in the extramural program and industry, we have been evaluating a variety of redox active NSAIDs in various models of cancer treatment and prevention. We have focused on NSAIDs that modified with anethole dithiolthione (ADT) a know cancer prevention agent that releases hydrogen sulfide. In addition we have developed novel NSAIDs that contain nitroxide that act like ROS scavengers and superoxide scavengers. The presence of the nitroxide greatly improved the tolerance from gut toxicity. In addition to inhibition of COX it also inhibited LOX thus being a complete ecosinoid inhibitor. 2) Phosphatase Agonist: We have begun to focus our effort on developing PP2A agonist. It was found from project one that NO and COX2 mediated much of the signaling through a variety of pathways that the tumor suppressor PP2A. We have not only identified the ADT like compounds but also APOE mimetic peptides. These peptides target the PP2A inhibitor protein SET which also inhibits the antimetastatic protein NM23. These results indicate that targeting SET maybe an important target node for the multi-pathway activation by Redox inflammation mechanism mediated by nitric oxide and ROS. 3) Immune modulators: One of the first projects is radiotherapy.